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ToxSci Advance Access published online on March 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi157
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received February 11, 2005
Accepted March 18, 2005

Biotransformation and Toxicokinetics

Reduction of Arsenate to Arsenite by Human Erythrocyte Lysate and Rat Liver Cytosol - Characterization of a Glutathione- and NAD-Dependent Arsenate Reduction Linked to Glycolysis

Balázs Németi 1 and Zoltán Gregus 1*

1 Department of Pharmacology and Pharmacotherapy, Toxicology Section, University of Pécs, Medical School

* To whom correspondence should be addressed.
Zoltán Gregus, E-mail: zoltan.gregus{at}aok.pte.hu


  Abstract

Reduction of arsenate (AsV) to the more toxic arsenite (AsIII) is of high toxicological importance, yet in vivo relevant enzymes involved have not been identified. Purine nucleoside phosphorylase (PNP) is an efficient AsV reductase in vitro, but its role in AsV reduction is irrelevant in vivo. Intact human red blood cells (RBC) possess an AsV reductase activity that is PNP-independent, diminished by depletion of glutathione (GSH), enhanced by oxidants of erythrocytic NAD(P)H, and is possibly linked to the lower part of the glycolytic pathway. In order to characterize this PNP-independent AsV reductase activity further, we examined the effects of GSH, inorganic phosphate, some inhibitors of glucose metabolism, glycolytic substrates, and pyridine as well as adenine nucleotides on AsV reduction in lysed RBC and rat liver cytosol in the presence of BCX-1777, a PNP inhibitor. In hemolysate, GSH enhanced AsV reduction in a concentration dependent manner, whereas phosphate inhibited it. Glycolytic substrates, especially fructose-1,6-bisphosphate and phosphoglyceric acids, improved AsV reductase activity. NAD, especially together with these substrates, strongly increased AsIII formation, whereas NADH strongly inhibited it. NADP and adenine nucleotides diminished, while 2-phosphoglycollate, which increases the breakdown of the RBC-specific compound 2,3-bisphosphoglycerate to 3-phosphoglycerate, doubled the AsV reductase activity. Although AsV reduction by the liver cytosol responded similarly to GSH, NAD, and glycolytic substrates as in the hemolysate, it was barely influenced by NADH, was diminished by 2-phosphoglycollate and stimulated by NADP. Collectively, hemolysate and rat liver cytosol possess a PNP-independent AsV reductase activity. This enzymatic activity requires GSH, NAD, and glycolytic substrates, and purportedly involves one or both of the two functionally linked glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase. In addition, the data presented here suggest that yet another PNP-independent AsV reductase resides in the hepatic cytosol. Although this latter enzyme remains unknown, identification of the AsV reductase depending on GSH, NAD, and glycolytic substrates is presented in the following paper.

Keywords: arsenate; arsenite; reduction; glutathione; glycolysis; NAD.
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B. Nemeti, I. Csanaky, and Z. Gregus
Effect of an Inactivator of Glyceraldehyde-3-Phosphate Dehydrogenase, a Fortuitous Arsenate Reductase, on Disposition of Arsenate in Rats
Toxicol. Sci., March 1, 2006; 90(1): 49 - 60.
[Abstract] [Full Text] [PDF]


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